PMID- 30521963 OWN - NLM STAT- MEDLINE DCOM- 20190503 LR - 20190503 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 66 DP - 2019 Jan TI - Ivabradine abrogates TNF-alpha-induced degradation of articular cartilage matrix. PG - 347-353 LID - S1567-5769(18)30693-3 [pii] LID - 10.1016/j.intimp.2018.11.035 [doi] AB - Ivabradine is most commonly used for the treatment of worsening cardiac failure in patients who cannot tolerate the maximum dose of beta-blockers or in whom treatment with beta-blockers is contraindicated. While ivabradine is regarded as a highly selective "funny current" (I(f)) inhibitor, the molecular mechanism behind the effect of this drug remains poorly understood. In the present study, we applied ivabradine in the context of osteoarthritis by treating primary human chondrocytes with tumor necrosis factor-alpha (TNF-alpha) and measuring degradation of the articular cartilage matrix as well as the expression of various enzymes and pro-inflammatory cytokines. Our results indicate that ivabradine significantly abrogated TNF-alpha-induced up-regulation of matrix metalloproteinase-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5 at both the gene and protein levels. Notably, ivabradine attenuated TNF-alpha-induced reduction of type II collagen and aggrecan at both the mRNA and protein levels. Also, we found that ivabradine inhibited the expression and secretion of interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) as well as the production of reactive oxygen species (ROS). Mechanistically, our results indicate that ivabradine abolished the activation of nuclear factor (NF-kappaB) by inhibiting nuclear translocation of NF-kappaB p65. Knockdown of HCN2 enhanced the protective effects of ivabradine against TNF-alpha- induced degradation of both type II collagen and aggrecan, suggesting that the inhibitory effects of ivabradine in ECM degradation might be mediated by HCN2. Our findings demonstrate that ivabradine may indeed have a potential application in preventing excessive degradation of the articular cartilage matrix, thereby preventing the pathological development and progression of osteoarthritis. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Xiang, Xianxiang AU - Xiang X AD - Department of orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215000, China; Dalian Jiuzhou Century Hospital, Dalian 116400, China. FAU - Zhou, Yantao AU - Zhou Y AD - Department of Orthopedics, The central Hospital of Enshi Autonomous Prefecture, Enshi 445000, China. FAU - Sun, Honglin AU - Sun H AD - Department of Internal medicine, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China. FAU - Tan, Shiping AU - Tan S AD - Department of orthopedics, Dalian Jiuzhou Century Hospital, Dalian 116400, China. FAU - Lu, Zhanbin AU - Lu Z AD - Department of orthopedics, Dalian Jiuzhou Century Hospital, Dalian 116400, China. FAU - Huang, Lixin AU - Huang L AD - Department of orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215000, China. Electronic address: szhuanglx@yeah.net. FAU - Wang, Weiming AU - Wang W AD - Department of orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China. Electronic address: oldpal@126.com. LA - eng PT - Journal Article DEP - 20181203 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Cardiovascular Agents) RN - 0 (Collagen Type II) RN - 0 (HCN2 protein, human) RN - 0 (Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels) RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-6) RN - 0 (NF-kappa B) RN - 0 (Potassium Channels) RN - 0 (RNA, Small Interfering) RN - 0 (Tumor Necrosis Factor-alpha) RN - 3H48L0LPZQ (Ivabradine) RN - EC 3.4.24.- (MMP13 protein, human) RN - EC 3.4.24.- (Matrix Metalloproteinase 13) RN - EC 3.4.24.17 (MMP3 protein, human) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - EC 3.4.24.82 (ADAMTS4 Protein) SB - IM MH - ADAMTS4 Protein/metabolism MH - Anti-Inflammatory Agents/*pharmacology MH - Cardiovascular Agents/pharmacology MH - Cartilage, Articular/*metabolism/pathology MH - Cells, Cultured MH - Chondrocytes/*drug effects MH - Collagen Type II/metabolism MH - Extracellular Matrix/metabolism MH - Humans MH - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics/*metabolism MH - Interleukin-1beta/metabolism MH - Interleukin-6/metabolism MH - Ivabradine/*pharmacology MH - Matrix Metalloproteinase 13/metabolism MH - Matrix Metalloproteinase 3/metabolism MH - NF-kappa B/metabolism MH - Osteoarthritis/*drug therapy MH - Potassium Channels/genetics/*metabolism MH - RNA, Small Interfering/genetics MH - Signal Transduction MH - Tumor Necrosis Factor-alpha/*metabolism OTO - NOTNLM OT - Aggrecan OT - Extracellular matrix OT - Ivabradine OT - Osteoarthritis OT - Type II collagen EDAT- 2018/12/07 06:00 MHDA- 2019/05/06 06:00 CRDT- 2018/12/07 06:00 PHST- 2018/09/19 00:00 [received] PHST- 2018/11/08 00:00 [revised] PHST- 2018/11/20 00:00 [accepted] PHST- 2018/12/07 06:00 [pubmed] PHST- 2019/05/06 06:00 [medline] PHST- 2018/12/07 06:00 [entrez] AID - S1567-5769(18)30693-3 [pii] AID - 10.1016/j.intimp.2018.11.035 [doi] PST - ppublish SO - Int Immunopharmacol. 2019 Jan;66:347-353. doi: 10.1016/j.intimp.2018.11.035. Epub 2018 Dec 3.